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(Circulation Research. 2007;101:137.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Disruption of Planar Cell Polarity Signaling Results in Congenital Heart Defects and Cardiomyopathy Attributable to Early Cardiomyocyte Disorganization

Helen M. Phillips, Hong Jun Rhee, Jennifer N. Murdoch, Victoria Hildreth, Jonathan D. Peat, Robert H. Anderson, Andrew J. Copp, Bill Chaudhry, Deborah J. Henderson

From the Institute of Human Genetics (H.M.P., H.J.R., V.H., J.D.P., B.C., D.J.H.), Newcastle University, Newcastle upon Tyne; Medical Research Council Mammalian Genetics Unit (J.N.M.), Harwell, Oxon; and Cardiac Unit (R.H.A.) and Neural Development Unit (A.J.C.), Institute of Child Health, University College London, UK.

Correspondence to Dr Deborah J. Henderson, Newcastle University, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. E-mail d.j.henderson{at}ncl.ac.uk

The Drosophila scribble gene regulates apical-basal polarity and is implicated in control of cellular architecture and cell growth control. Mutations in mammalian Scrib (circletail; Crc mutant) also result in abnormalities suggestive of roles in planar cell polarity regulation. We show that Crc mutants develop heart malformations and cardiomyopathy attributable to abnormalities in cardiomyocyte organization within the early heart tube. N-Cadherin is lost from the cardiomyocyte cell membrane and cell–cell adhesion is disrupted. This results in abnormalities in heart looping and formation of both the trabeculae and compact myocardium, which ultimately results in cardiac misalignment defects and ventricular noncompaction. Thus, these late abnormalities arise from defects occurring at the earliest stages of heart development. Mislocalization of Vangl2 in Crc/Crc cardiomyocytes suggests Scrib is acting in the planar cell polarity pathway in this tissue. Moreover, double heterozygosity for mutations in both Scrib and Vangl2 can cause cardiac defects similar to those found in homozygous mutants for each gene but without other major defects. We propose that heterozygosity for mutations in different genes in the planar cell polarity pathway may be an important mechanism for congenital heart defects and cardiomyopathy in humans.

Key Words: cardiac development • cardiomyopathy • congenital heart defects • planar cell polarity • Scrib

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